Bacteria and their toxins have been investigated for their anticancer activities. In the 1970s, bacteria (such as non-pathogenic Clostridium) were used for the treatment of malignant brain tumors, but the tumors recurred in these brain tumor patients. More than 100 microorganisms have been studied for their potential anticancer activities, and many bacteria have growth specificity for tumors that is 1000 times greater than for other tissue.
Receptor-specific biological agents have an advantage over traditional chemotherapy cancer drugs in that they exhibit greater disease specificity and lower toxicity. While their anti-tumor activities make many bacteria attractive therapeutic agents, there are inherent risks to administering live bacteria to humans. A safer and more effective strategy has been to use biological toxins, specifically from bacteria, as therapeutic agents. Bacterial toxins are not only toxic, but are also highly specific for certain cell types, or can be engineered to be specific by fusing the toxin to other molecules. Many bacterial toxins are able to enter mammalian cells where they exert their toxic effects. Because of extensive evolutionary adaptation between bacteria and their hosts, bacteria have become very good at “developing” highly effective toxins.
Each year, more than 60,500 people die of hematologic malignancies (leukemia, lymphoma, myeloma) with more than 110,000 new annual diagnoses in the US alone. B-cell related cancers include Hodgkin's, and non-Hodgkin's lymphoma (NHL) (e.g., mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma). Current treatment for these cancers includes the use of synthetic compounds that target the cell division process of nearly all cells of the body, not just the cancerous ones. As a result, devastating side effects are all too common. Furthermore, a significant percentage of patients eventually show resistance to many of the drugs, thus rendering treatment largely ineffective or susceptible to the incidence of relapse and refractory disease for many patients remains high. For example, MCL is a deadly and incurable disease and even with new therapeutic approaches, the mean overall survival rate remains approximately 3-4 years. For FL, the most common indolent NHL, there is no consensus treatment protocol and the disease is considered incurable. Approximately 30-40% of DLBCL patients still die from this cancer. Most of these deaths result from therapeutic resistance in the cancerous cells when the disease recurs. Thus, there is a great need for novel agents that target B-cell lymphomas. While the drugs currently in use are toxic for cells, they are not highly specific. A new class of therapeutic agents for the treatment of hematologic malignancies, and cancer in general, includes drugs that exhibit specificity for predominantly the cancerous cell type. Examples of targeted therapeutics include Rituximab, which is a monoclonal antibody against B-lymphocytes, and Mylotarg, an antibody-anti-tumor antibiotic fusion directed against cells of myelomonocytic lineage.
Actinobacillus actinomycetemcomitans is a Gram negative pathogen that inhabits the oral cavities of humans. A. actinomycetemcomitans is the etiologic agent of localized aggressive periodontitis (LAP), a rapidly progressing and destructive disease of the gingiva and periodontal ligaments. Among its many virulence factors, A. actinomycetemcomitans produces an RTX (repeats in toxin) leukotoxin. A. actinomycetemcomitans leukotoxin is an approximately 115 kDa protein that kills specifically leukocytes of humans and Old World Primates. Leukotoxin (LtxA) is part of the RTX family that includes E. coli a-hemolysin (H1yA) and Bordetella pertussis adenylate cyclase (CyaA). Leukotoxin may play an important role in A. actinomycetemcomitans pathogenesis by helping the bacterium destroy gingival crevice polymorphonuclear leukocytes (PMNs) and monocytes, resulting in the suppression of local immune defenses.
LtxA binds leukocyte function antigen (LFA-1) on white blood cells (WBCs) and induces cell death via apoptosis or necrosis. It has been found that LtxA preferentially targets WBCs with high levels of activated LFA-1, a characteristic of many leukemias and lymphomas. In many ways, LtxA represents a natural version of an immunotoxin since it is both toxic and highly specific within the same molecule. Advantages of native LtxA over artificially-engineered molecules include greater stability, increased specificity, and lower toxicity.
The U.S. FDA recently issued an initiative and draft guidelines to promote the development of experimental therapeutics in combination to improve the efficacy and safety profile of cancer drug regimens because many of the standard chemotherapeutic agents are highly cytotoxic that elicit severe side effects. Thus, there remains a need to develop new cancer drugs and therapy that are less toxic and effective to treat cancer.